ABSTRACT TB is the leading cause of death among persons with HIV worldwide. Globally, approximately 25% of persons with HIV are heavy drinkers, and heavy alcohol use is associated with a 3-fold higher risk of TB disease compared to no alcohol use, thus HIV-infected persons who drink alcohol are at high risk for TB. Six months of isoniazid (INH) preventive therapy (IPT) reduces TB incidence and mortality by 30-50% above the positive impact of antiretroviral therapy (ART). However, INH can be toxic to the liver, and thus many heavy alcohol users in resource-limited settings such as east Africa are not offered IPT. In addition, heavy alcohol users have poorer ART adherence and data suggest decreased IPT adherence as well. Thus interventions are needed to both decrease alcohol use and increase IPT adherence, and thereby reduce INH toxicity, TB morbidity and mortality in this high-risk population. The use of incentives to promote healthy behavior has been shown to be a highly effective approach for reducing substance use and for improving adherence to HIV and TB regimens in high-income countries. Reducing alcohol use may create a window for safe and effective IPT use by decreasing hepatotoxicity and increasing IPT adherence; however, additional interventions for IPT adherence may be needed. The use of incentives conditional on reduced alcohol use or increased INH adherence in resource-limited settings has been previously limited by the lack of reliable, rapid tests for these behaviors. Recent technological advances allow for point of care (POC) urine testing for recent alcohol use with an ethyl glucuronide (EtG) dipstick that is positive for 3 days after heavy drinking, and INH pill-taking using the IsoScreen urine test to test for 24-hour INH ingestion, thereby creating an opportunity to test incentive-based interventions during IPT among heavy drinkers. We propose leveraging two established cohorts of persons with HIV in Uganda for a randomized 2x2 factorial trial among HIV/TB co-infected adults with heavy alcohol use (n=800 persons. 400 each U01 cohort). Aim 1 is to determine whether economic incentives contingent on reduced alcohol use assessed by POC EtG tests conducted at INH refill visits reduces heavy alcohol use over six months of IPT compared to the control. Aim 2 is to determine whether economic incentives contingent on INH positive POC urine tests at these visits compared to the control increases IPT adherence over six months. Aim 3 is to examine the longer-term impact of the intervention on HIV virologic suppression, and examine mediators of an effect. Primary outcomes will be self-reported heavy alcohol use augmented by phosphatidylethanol (PEth) concentrations, and INH adherence, measured using medication event monitoring system (MEMS), with additional measurements of pill ingestion by INH levels in hair samples. Using incentive- based interventions to reduce alcohol use and increase medication safety in low-income settings is novel. This study to optimize IPT in HIV/TB co-infected drinkers will provide new information on low-cost strategies to reduce alcohol use and increase IPT adherence in low-income countries.